Cancer and infectious disease are significant health problems throughout the world. Although advances have been made in detection and therapy of these diseases, no vaccine or other universally successful method for prevention or treatment is currently available. Current therapies, which are generally based on a combination of chemotherapy or surgery and radiation, continue to prove inadequate in many patients.
Identification of human tumor antigens is critical to the development of immune-based treatments targeting tumors, such as cancer vaccines. Tumor antigens are proteins that are immunogenic in patients with cancer but not in subjects who are non-tumor bearing. Thus, the pre-existent immune response to tumor associated proteins has been exploited as a tool for antigen discovery. Melanoma antigens have been identified by screening tumor-associated proteins encoded in reporter cells with autologous T cells specific for the patient's tumor. T cell-based methods of antigen discovery are laborious and require autologous tumor both for the generation of the reporter cells as well as the tumor specific T cells used to detect responses.
Cancer patients also have antibody immunity directed against tumor associated proteins and more recent methods of antigen discovery have focused on the use of tumor specific antibodies as probes for screening potential tumor antigens. Genomic and proteomic techniques, applied to the discovery of tumor antigens, have allowed immunogenic proteins to be identified without the use of autologous tumor cells. Both approaches utilize a humoral immune response to screen for tumor specific antigens. Many of the tumor specific IgG antibody responses identified in this fashion are high titer implying recognition by T helper cells. Antigens discovered using IgG antibody immunity as a screening tool can be considered to be recognized by the T helper cell repertoire and, potentially, cytotoxic T cells (CTL). High-throughput serologic antigen discovery methods have resulted in dozens of tumor antigens being identified, however, the function or relevance of many of these immunogenic proteins is not known.
Self-proteins have been identified as tumor antigens. These proteins are not mutated in any way, but are clearly immunogenic in patients with cancer. Many of these proteins are present at much higher concentrations in malignant cells than in the normal cells with which they are associated. Overexpression of self-proteins may allow subdominant epitopes to be presented in the MHC in high enough density to elicit a T cell response. Indeed, the peptide repertoire display in the MHC when a protein is overexpressed may be distinctly different from the peptides present in resting MHC where that same protein is present at basal levels. Protein overexpression in a cancer cell, therefore, may result in making that protein a tumor antigen. The demonstration of detectable immunity directed against a self-tumor antigen suggests that some level of immunologic tolerance has been circumvented, that the ability to recognize the antigen is within the realm of the human T cell repertoire, and that the immune response may be boosted by active immunization.
The success of any targeted cancer therapy depends on eradicating cells that express essential targets, i.e. proteins that maintain or impact the malignant phenotype, and cancer vaccines are no exception. HER-2/neu is a biologically relevant tumor antigen and aberrant signaling via the receptor is an important growth regulator for breast cancers expressing the protein. However, multiple oncogenic pathways are implicated in breast cancer progression; thus, additional essential immunologic targets need to be defined to enhance the therapeutic efficacy of immunization and impact tumor growth.
The insulin like growth factor (IGF) pathway is emerging as an important growth regulator in breast cancer. IGF signaling stimulates proliferation and inhibits apoptosis in cancer cells (Pollak, M. N., et a. 2004. Nat Rev Cancer 4:505-518). In particular, insulin like growth factor receptor binding protein 2 (IGFBP-2) has been shown to be increasingly overexpressed during breast cancer progression (Busund, L. T., et al. 2005. J Clin Pathol 58:361-366). Recent studies have suggested that not only does IGFBP-2 have a direct proliferative effect on tumor growth, the protein is a regulator of PI3K/Akt activation and may facilitate the malignant transformation (Mehrian-Shai, R., et al. 2007. Proc Natl Acad Sci USA 104:5563-556811-13; Martin, J. L., and Baxter, R. C. 2007. Endocrinology 148:2532-2541; Perks, C. M., et al. 2007. Oncogenel 26(40):5966-572). Stimulating immune eradication of IGFBP-2 overexpressing breast cancer cells may potentially impact cancer progression.
Due to the limitations and challenges posed by currently available approaches to cancer diagnosis and therapy, there is a need in the art for the development of alternative methods and compositions. The present invention fulfills this need, and further provides other related advantages.